Modafinil (also known by the brand names Provigil, Alertec, Modavigil, and others) is a eugeroic substance of the benzhydryl class that produces wakefulness-promoting and stimulant effects when administered. It is commonly used to enhance cognition, reduce fatigue, and increase alertness in both medical and non-medical contexts.

Modafinil is approved by the U.S. Food and Drug Administration for the treatment of obstructive sleep apnea, shift work sleep disorder and narcolepsy.[1] However, studies have shown that modafinil may also be useful off-label for alleviating the symptoms of depression,[2], bipolar disorder,[3] Parkinson's disease,[4] seasonal depressive disorder,[5] ADHD,[6] and various other conditions which have fatigue as a symptom.

Chemistry

Modafinil is a synthetic molecule of the benzhydryl class. Benzhydryl compounds are comprised of two benzene rings attached to a single carbon molecule. Modafinil is classified as a sulphinyl benzhydryl molecule, as it also contains a sulphinyl group, a sulphur molecule double-bonded to an oxygen molecule, attached to the carbon of the benzhydryl group. From this sulphur group at R2, an acetamide group is bound at its free carbon through a carbonyl group to a terminal amine group. Modafinil is structurally analogous to fluorafinil, another benzhydryl stimulant.

While modafinil is a racemic mixture, a similar medication, armodafinil, consists of only the (−)-(R)-enantiomer of modafinil.

Modafinil and its R-enantiomer, armodafinil, increase both norepinephrine (NE) and dopamine (DA), possibly via their blockade of both the NE and DA reuptake transporters (NET and DAT, respectively). The actions of NE at alpha-adrenergic receptors and DA at dopamine D2 receptors are thought to contribute to the wake-promoting properties of modafinil. Orexin is a key component of the arousal system; thus, the hypothesized action of modafinil on the orexinergic system may help increase alertness. Additionally, modafinil may indirectly increase histamine, either by reducing GABAergic inhibition of histaminergic neurons or via actions at orexinergic neurons. The increase in histamine may contribute to both the wake-promoting effects of modafinil as well as the potential of modafinil to increase alertness.[7][9][11]

In genetically engineered mice lacking the dopamine transporter (DAT), modafinil lacked wake-promoting activity, suggesting that this activity was DAT-dependent. However, the wake-promoting effects of modafinil, unlike those of amphetamine, were not reduced by the dopamine receptor antagonisthaloperidol in rats. In addition, alpha-methyl-p-tyrosine, an inhibitor of dopamine synthesis, blocks the action of amphetamine but does not block locomotor activity induced by modafinil.

The effects listed below are based upon the subjective effects index and personal experiences of PsychonautWikicontributors. These effects should be taken with a grain of salt and will rarely (if ever) occur all at once, but heavier doses will increase the chances of inducing a full range of effects. Likewise, adverse effects become much more likely on higher doses and may include serious injury or death.

Physical effects

Stimulation - In terms of its effects on the user's physical energy levels, modafinil is commonly considered to be stimulating and energetic, but can be considered as much less stimulating when compared to amphetamine. This stimulation encourages physical movement and activities such as running, playing sports, socializing, and/or exercising. The particular style of stimulation which modafinil presents can result in jaw clenching, teeth grinding, or other involuntary movements comparable to that of traditional stimulants at high doses, but are manifested much less consistently and intensely when compared to amphetamine or cocaine.

Appetite suppression - The above components are also accompanied by a suppression of appetite which is usually less intense in strength in comparison to the appetite suppression experienced with amphetamine.

Dehydration - Dehydration and dry mouth commonly occur due to an increase in motivation to engage in physical activities as well as an increased sense of focus which causes one to forget to drink water.

Headaches - In terms of physical discomfort, modafinil can cause headaches especially if dehydrated, if you have not eaten food, or if you have been sitting in an awkward position for an extended period of time focused intensely on a task.

Body odor alteration - Modafinil can leave a very distinct smell of sulfur in one's urine. This is likely because modafinil, being a member of the sulphinyl benzhydryl chemical class, contains sulfur in its chemical makeup.[12]

Experience reports

Toxicity and harm potential

The long-term safety and effectiveness of modafinil as a drug of regular usage have not been determined.[13]

Anecdotal reports from people who have tried modafinil suggest that there do not seem to be any negative health effects attributed to simply trying this substance at low to moderate doses by itself or using it sparingly (but nothing can be completely guaranteed).

It is worth noting that as this compound is a commonly prescribed pharmaceutical, it is considerably less likely to have unpredictable adverse health effects than the typical research chemical. Nevertheless, it is strongly recommended that one use harm reduction practices if using this substance.

Lethal dosage

The median lethal dose at which 50% of participants die (LD50) from modafinil for human beings has never been reached. No life-threatening effects have taken place in clinical trials involving the administration of 1000mg to 1600mg of modafinil per day for 7 to 21 consecutive days. Intentional acute overdoses of 4500mg and 4000mg in two adult subjects and an accidental ingestion of 800mg by a three-year-old child did not result in any life-threatening effects or death.[14] After overdosing on 5000mg of modafinil in a suicide attempt, a fifteen-year-old female reported a severe headache, nausea, and tachycardia, but did not appear to have any lethal or long-term effects.[15]

Tolerance and addiction potential

The chronic use of modafinil can be considered as not addictive with a low potential for abuse. It does not seem to be capable of causing psychological dependence among most users.[citation needed]

Tolerance to many of the effects of modafinil develops with prolonged and repeated use. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption). Modafinil may present a cross-tolerance with all benzhydrylnootropics, meaning that after the consumption of modafinil, all related eugeroic compounds such as armodafinil and adrafinil will display a reduced effect.

Dangerous interactions

Although many psychoactive substances are reasonably safe to use on their own, they can quickly become harmful and even life-threatening when taken with other substances. The following section lists some known dangerous combinations, but it may not include all of them. Furthermore, a combination that seems to be harmless in low doses can still greatly increase the risk of injury or death when the doses are slightly increased. Independent research should always be conducted to ensure that a combination of two or more substances is safe to consume. Some interactions listed have been sourced from Tripsit.

MDMA - The neurotoxic effects of MDMA may be increased when combined with other amphetamines.

Alcohol - Alcohol can be dangerous to combine with stimulants due to the risk of accidental over-intoxication. Stimulants mask the sedative effects of alcohol, which is the main factor people use to assess their degree of intoxication. Once the stimulant wears off, the depressant effects of alcohol are left unopposed, which can result in blackouts and respiratory depression. If combined, one should strictly limit themselves to only drinking a certain amount of alcohol per hour.

DXM - Combinations with DXM should be strictly avoided due to DXM's effects on serotonin and dopamine reuptake. This can lead to panic attacks, hypertensive crisis, or serotonin syndrome.

MXE - Combinations with MXE may dangerously elevate blood pressure and increase the risk of psychosis.

Tramadol - Tramadol lowers the seizure threshold.[16] Combinations with stimulants may further increase this risk.

MDMA - The neurotoxic effects of MDMA may be increased when combined with other stimulants.

Hormonal Birth Control - Modafinil reduces the effectiveness of hormonal birth control for up to a month after use by increasing the activity of the enzyme CYP3A4/5.[18] Notably, the same enzyme is inhibited by grapefruit juice.[19]

Legal status

Modafinil is legally approved for medical purposes worldwide. However, it is illegal to sell and possess in most countries without a prescription.

Australia: Modafinil is listed as a Schedule 4 (prescription only) drug in Australia and it can be prescribed sleep apnea and narcolepsy.[20]

Canada: Modafinil is listed as a Schedule F prescription drug in Canada and can be prescribed for human and veterinary use.[21]

Germany: Modafinil is a prescription medicine, according to Anlage 1 AMVV.[22]

United Kingdom: Modafinil is a licensed prescription-only medicine (POM) in the United Kingdom.[24] It is not a criminal offence to possess this medicine without a valid prescription. This medicine can legally be obtained with a valid prescription or through legal import of the medicine for personal use as outlined in Section 13 of the Medicines Act 1968.[25]

United States: In the United States, modafinil is a Schedule IV controlled substance. It is illegal to buy, sell, or possess the drug without a prescription or DEA license.[26]